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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Micro RNA-379 couples glucocorticoid hormones to metabolic dysfunction in diabesity

ABSTRACT: In metabolic control, GC signaling acts as a major counter-regulatory system against insulin action, and aberrantly elevated GC activity is tightly linked to major components of the so-called Metabolic Syndrome, including obesity, insulin resistance, hyperglycemia, and systemic dyslipidemia. Here we identify the hepatic induction of the conserved microRNA (miR)-379/410 genomic cluster as a key component of GC/GR-driven metabolic dysfunction in M-bM-^@M-^\diabesityM-bM-^@M-^] Microarray data were utilized to screened for differentially regulated miRNAs between wt and db/db and between wt and GR Knockdown mice For wt vs. db/db: mice were fasted for 24 hours and refed for 6 hours; For GR-dependent miRNAs: mice were treated with rAAV delivering either control or GR-directed miRNA for the knockdown of the GR specifically in the liver.

ORGANISM(S): Mus musculus

SUBMITTER: Carsten Sticht

PROVIDER: E-GEOD-55245 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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micro RNA-379 couples glucocorticoid hormones to metabolic dysfunction in diabesity

Project description:In metabolic control, GC signaling acts as a major counter-regulatory system against insulin action, and aberrantly elevated GC activity is tightly linked to major components of the so-called Metabolic Syndrome, including obesity, insulin resistance, hyperglycemia, and systemic dyslipidemia. Here we identify the hepatic induction of the conserved microRNA (miR)-379/410 genomic cluster as a key component of GC/GR-driven metabolic dysfunction in “diabesity” Microarray data were utilized to screened for differentially regulated miRNAs between wt and db/db and between wt and GR Knockdown mice

2014-10-15 | GSE55245 | GEO

Skin gamma delta T cells in Obesity

Project description:Epithelial cells provide an initial line of defense against damage and pathogens in barrier tissues such as the skin; however this balance is disrupted in obesity and metabolic disease. Skin gamma delta T cells recognize epithelial damage and release cytokines and growth factors that facilitate wound repair. To determine the impact of obesity and metabolic disease on skin gamma delta T cells, we isolated skin gamma delta T cells from 10-week old C57BLKS/J lean db/+ and obese db/db animals for further study. Due to a deficiency in the leptin receptor (db), homozygous db/db animals do not process satiety signals, continually eat and develop severe obesity and metabolic disease. Skin gamma delta T cells isolated from these animals were compared for changes in mRNA expression using microarray. We have determined that obesity and metabolic disease negatively impacts homeostasis and functionality of skin gamma delta T cells, rendering host defense mechanisms vulnerable to injury and infection. The goal of this experiment was to compare skin gamma delta T cells in a control mouse to skin gamma delta T cells isolated from an obese mouse to see what homeostatic changes occur in obesity and metabolic disease. gamma delta T cells were isolated from two 10-week old lean db/+ control and two 10-week old obese db/db animals for comparison. We wanted to determine which growth factors and signaling pathways were altered in skin gamma delta T cells residing in the obese environment.

2010-07-30 | E-GEOD-22196 | biostudies-arrayexpress

Characterization of a new selective glucocorticoid receptor modulator with anorexigenic activity

Project description:Obesity, a worldwide epidemic, leads to various metabolic disorders threatening human health. In response to stress or fasting, glucocorticoid (GC) levels are elevated to promote food intake. This involves GC-induced expression of the orexigenic neuropeptides in agouti-related protein (AgRP) neurons of the hypothalamic arcuate nucleus (ARC) via the GC receptor (GR). Here, we report a selective GR modulator (SGRM) that suppresses GR-induced transcription of genes with non-classical glucocorticoid response elements (GREs) such as Agrp-GRE, but not with classical GREs, and via this way may serve as a novel anti-obesity agent. We have identified a novel SGRM, 2-O-trans-p-coumaroylalphitolic acid (Zj7), a triterpenoid extracted from the Ziziphus jujube plant, that selectively suppresses GR transcriptional activity in Agrp-GRE without affecting classical GREs. Zj7 reduces the expression of orexigenic genes in the ARC and exerts a significant anorexigenic effect with weight loss and increased energy expenditure in both high-fat diet-induced obese and genetically obese db/db mouse models. Transcriptome analysis showed that Zj7 represses the expression of a group of orexigenic genes including Agrp and Npy induced by the synthetic GR ligand dexamethasone (Dex) in the hypothalamus. Overall, our studies demonstrate that selectively targeting the orexigenic action of GR in AgRP neurons is a promising approach for the treatment of metabolic disorders with fewer side effects.

2024-04-10 | GSE260739 | GEO

Expression analysis in pancreatic and liver tissues of diabetic db/db mice in response to dietary supplementation with selenate

Project description:Investigation of gene expression level changes in pancreatic and liver tissues of diabetic db/db mice supplemented with selenate, compared to the diabetic db/db mice administered placebo. Fasting blood glucose levels increased continuously in diabetic db/db mice administered placebo (DMCtrl) but decreased gradually in selenate-supplemented diabetic db/db mice (DMSe) and approached normal values when the experiment ended. The size of pancreatic islets increased, causing the plasma insulin concentration to double in DMSe mice compared with that in DMCtrl mice. Two six chip studies using total RNA respectively isolated from pancreatic and liver tissues of three selenate-supplemented diabetic db/db mice, and three diabetic db/db mice administered placebo.

2014-03-07 | E-GEOD-55636 | biostudies-arrayexpress

Title Page Cardiac Gene Therapy Rescues Diabetic Cardiomyopathy and Lowers Blood Glucose

Project description:Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intra-cardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalizes components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalizes insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescues cardiac lusitropy, improves exercise intolerance, and ameliorates hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy, and also improve systemic glycemic control.

2023-10-24 | PXD044236 | Pride

Palmitoylation couples insulin hypersecretion with β-cell failure in diabetes

Project description:Hyperinsulinemia often precedes type 2 diabetes but its role in disease progression is unknown. Palmitoylation, a protein modification implicated in regulated exocytosis, is reversed by acyl-protein thioesterase 1 (APT1). We found altered APT1 biology in pancreatic islets from humans with type 2 diabetes, and APT1 knockdown in nondiabetic human islets caused insulin hypersecretion. Chow fed global and islet specific APT1 knockout mice had enhanced glucose tolerance due to islet autonomous increased glucose-stimulated insulin secretion. APT1 deficiency did not affect islet calcium dynamics but prolonged insulin granule fusion. Using palmitoylation proteomics, we identified Scamp1 as an APT1 substrate that localized to insulin secretory granules. Knockdown of Scamp1 caused insulin hypersecretion. APT1 deficient insulinoma cells subjected to nutrient excess had increased apoptosis, and expression of a mutated Scamp1 incapable of being palmitoylated in APT1 deficient cells rescued insulin hypersecretion and nutrient induced apoptosis. Compared to APT1 sufficient controls, high fat fed islet specific APT1 knockout mice and global APT1 deficient db/db mice showed increased -cell failure. These findings suggest that the depalmitoylation enzyme APT1 is regulated in human islets, and that APT1 deficiency causes insulin hypersecretion leading to -cell failure, modeling the evolution of some forms of human type 2 diabetes.

2023-11-05 | PXD038554 | Pride

Profiling pancreatic islets from obese db/db and lean control db/+ mice

Project description:This program addresses the molecular basis of beta-cell failure associated with the development of type 2 diabetes in the db/db mice. Specifically, which genes are differentially expressed in pancreatic islets of the db/db mice compared to the control db/+ mice? The db/db mice islets profiling data was analyzed by identifying genes that were up- and down-regulated at selected p value and fold change in the islets of db/db mice compared to the corresponding db/+ controls.

2013-03-22 | E-GEOD-31953 | biostudies-arrayexpress

Profiling epididymal white adipose tissue (eWAT) from obese db/db and lean control db/+ mice

Project description:This program addresses the gene signature associated with the development of type 2 diabetes in the db/db mice. Specifically, which genes are differentially expressed in adipose tissue of the db/db mice compared to the control db/+ mice? The db/db mice eWAT profiling data was analyzed by identifying genes that were up- and down-regulated at selected p value and fold change in the eWAT of db/db mice compared to the corresponding db/+ controls.

2013-03-22 | E-GEOD-38082 | biostudies-arrayexpress

Gene expression of BAT from GRBATKO mice exposed to cold

Project description:GRBATKO_BAT_COLDEXPOSURE Aberrant activity of the glucocorticoid (GC)/glucocorticoid receptor (GR) endocrine system has been linked to obesity-related metabolic dysfunction. Traditionally, the GC/GR axis has been believed to play a crucial role in adipose tissue formation and function in both, white (WAT) and brown adipose tissue (BAT). While recent studies have challenged this notion for WAT, the contribution of GC/GR signaling to BAT-dependent energy homeostasis remained unknown. Here, we have generated and characterized a BAT-specific GR knockout mouse (GRBATKO), for the first time allowing to genetically interrogate the metabolic impact of BAT GR. The HPA axis in GRBATKO mice was intact, as was the ability of mice to adapt to cold. BAT GR was dispensable for the adaptation to fasting-feeding cycles and the development of diet-induced obesity. In obesity, glucose and lipid metabolism, insulin sensitivity, and food intake remained unchanged, aligning with the absence of changes in thermogenic gene expression. Together, we demonstrate that the GR in UCP1-positive BAT adipocytes plays a negligible role in systemic metabolism and BAT function, thereby opposing a long-standing paradigm in the field.

2019-08-26 | GSE135544 | GEO

Glucocorticoid Activation of Anti-Inflammatory Macrophages in Coordination with STAT6 Protects Against Insulin Resistance

Project description:Deletion of the GC receptor (GR) in macrophages in mice, aggravates obesity-related insulin resistance, by reducing anti-inflammatory macrophages, and enhancing adipose tissue inflammation. Consequently, the reduction of anti-inflammatory macrophages leads to exaggerated adipose tissue lipolysis and severe hepatic steatosis. Mechanistically, macrophages deficient for GR show a diminished response to IL-4 driven anti-inflammatory polarization, due to disruption of an epigenetic crosstalk between GC and IL-4 signaling involving synergistic loading of GR and STAT6. Our results demonstrate that GR plays an important role in macrophage polarization during obesity by limiting adipose tissue inflammation and lipolysis to promote insulin sensitivity

2022-09-01 | GSE200371 | GEO

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